L1 Flashcards
How drugs cross the membrane?
- Passive diffusion
- Pinocytosis
- Aqueous pores
Passive diffusion
Drugs must be sufficiently hydrophobic to penetrate membranes but then pass through the aqeuous intracellular env and not be trapped in the membrane.
What is Fick’s Law?
Simple diffusion if dependent on the permeability of the membrane and the conc. gradient
- The rate at which the drug will diffuse through the membrane is dependent on the conc.
Pinocytosis
Pinching off membrane relevant for several protein drugs
Aqueous pores
Small drugs are able to pass through
Importance of drug ionisation
Ionisation influences the extent of drug movement between aqueous env. and lipid env.
Strong acids/ bases ionised at any pH - but these are few drugs
Weak acids and bases- extent of ionisation depends on pH of aqueous env. E.g. for a weakly acidic drugs in an acidic env. will suppress ionsiation, thus will favour diffusion through a membrane
Ionised or neutral form prefered
neutral is favoured and moves across membrane. Thus pH can influence the relative conc. of the neutral form of the drug
How does tissue pH affect drug disposition
E.g. aspirin (pH 3.5)
stomach 2.2 and intestine of 7..5
Aspirin would be neutral in the stomach and thus penetrate through the membrane. However in the small intestines, aspirin would be ionised thus absorption would not be favoured.
Influx transporters
- Solute carrier transports
- structure
- main role is transport anions and cations across membranes
- also mediate uptake many drugs
Structure: - consists of 12-transmembrane domains
- several intracellular and extracellular loops that orient the transporter in the membrane
Bioavailability
the amount of drug that is able to produced inside the body after administration and reaches the systemic circulation
intravenous dose is 1
Oral
- two mechanisms
bioavailability is decreased, drug is not absorbed
- First pass clearance (liver)
- presystemic metabolism in intestine
First pass hepatic clearance
Drug is absorbed in the portal circulation –> liver
- Liver is where biotransformation occurs
- Blood in portal vein before liver is conc. however after the drug is less conc. thus less will get in circulation
- Hepatic extraction is high when drug is extensively metabolised
Presystemic metabolism in intestine
Enterocytes contain biotransformation enzymes which are able to begin the process of the drug degradation
- after passing through the enterocyte, conc. of the drug will be reduces as the drug has been extensively metabolised.
Methods which avoid first-pass clearance
- Eyedrops
- Sublingual
- rectal adminsitration
- dermal delivery
This is because these methods tend to bypass the liver before reaching their target
Protein binding - can free drugs or drug-protein complex move across
only free drugs can move across
Plasma protein binding and free fraction of drug
- plasma proteins limit the free drug conc.
- these proteins bind loosely to the drug before entering system
- 1% of drug is in free form
- only free drugs can move across membrane
Protein binding to drug - Serum albumin
in some liver diseases, the albumin synthesis is decreased, thus less protein are binding to the drug. Thus more free form of the drug is able to move across. Thus instead 1% of drug being absorbed, there will be 5% which increases the dose of the drug and can be toxic.
A1-acidglycoprotein (AAG) bind to basic drugs
An inflammatory disease can cause production of more AAG, thus more AAG binding to the drug, thus less free form. Hence less is able to be absorbed thus drug is not as effective.
Bioavailability
AUC oral/ AUC intravenous
Cmin define
conc. of drug within limits during therapy
Biotransformation does what to lipophilicity
decreases. But at the same time increases water solubility
How does the body eliminate drugs? Simple answer
Biotransformation enzymes convert the lipid soluble chemicals to soluble chemicals (more polar), thus easily eliminated. Some metabolities are less active but some drugs are prodrugs that require metabolic activation.
Lipophillic character of drug
- Drugs must be lipophilic to penetrate membranes
- thus a drug will have lipid-like and aqueous phases
Partition coefficient (P)
the ratio of conc. in the lipid/ aqueous phase
where does biotransformation occur
mainly liver but also can occur in lungs, kidney, intestine, skin
Phase I reactions
convert lipophlic chemical into a more polar substance. Thus through oxidation, reduction or hydrolysis get a new functional group
Cytochromes P450 (CYPs)
The major class of phase I biotransformation enzymes
What do Cytochromes P450 act on?
diverse substrates (low substrate specificity)
Structure of CYP
- have a haem group involved in oxygen activation
- the polypeptide chain differs between CYPS and control substrate specificity
- Each CYP is encoded by a different gene
- The variation in the AA will influence function of enzyme
